Active transepithelial Cl − ‐secretion promotes hydrostatic lung edema

Hydrostatic lung edema evolves from increased fluid filtration and inhibition of epithelial Na + channels (ENaC) that facilitate alveolar fluid clearance. Recently, we identified alveolar fluid secretion (AFS) as new key component in edema formation. Here, we tested whether Cl − secretion via cystic fibrosis transmemberane conductance regulator (CFTR) and Na + ‐K + ‐Cl − cotransporter 1 (NKCC1) may mediate AFS at elevated left atrial pressure (P LA ) and may be induced by inhibition of ENaC. In isolated lungs, we quantified AFS by a double indicator dilution technique, and transepithelial Cl − flux by radionuclide tracing and alveolar Cl − imaging. P LA elevation induced lung edema and AFS that coincided with transepithelial Cl − secretion and alveolar Cl − influx. These effects were blocked by inhibitors of CFTR, NKCC or Na + ‐K + ‐ATPase, and CFTR −/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride at physiological P LA induced AFS and Cl − secretion that were again CFTR‐, NKCC‐ and Na + ‐K + ‐ ATPase dependent. We conclude that transepithelial Cl − and fluid flux reverse from absorptive to secretory mode at hydrostatic stress as a result of ENaC inhibition, and are mediated by NKCC and CFTR.